Is there evidence to support alternate-day dosing of oral iron for the treatment of iron deficiency anemia?

Background
Iron is an essential nutrient required for numerous physiological processes, including oxygen transport and energy metabolism.1,2 The majority of iron in the body is incorporated into hemoglobin within red blood cells, while smaller amounts circulate bound to transferrin or are stored as ferritin and hemosiderin, primarily in the liver and spleen.1,3 The body lacks a mechanism for active iron excretion; therefore, iron homeostasis is tightly regulated at the level of dietary uptake in the gut.1 Hepcidin, a peptide hormone produced by the liver, plays a key role in the intestinal absorption and systemic distribution of iron.1,2 Elevated hepcidin levels inhibit intestinal iron absorption by inducing degradation of ferroportin, the body’s only known iron exporter responsible for releasing intracellular iron into the circulation. Conversely, low hepcidin levels preserve ferroportin expression, thereby promoting iron absorption and systemic iron mobilization.

Iron deficiency is the most common nutritional disorder worldwide and a leading cause of anemia, resulting in fatigue, impaired cognitive function, and reduced quality of life.3-5 In iron deficiency anemia (IDA), hepcidin suppression facilitates increased iron absorption; however, oral iron supplementation transiently raises hepcidin levels for up to 48 hours, which can negatively influence the absorption of subsequent doses.1,4,5 This physiologic response has prompted interest in dosing strategies that optimize the bioavailability of oral iron while minimizing gastrointestinal (GI) adverse effects (AEs) that often compromise adherence.2,4,5 Dietary and administration strategies mentioned in the literature include dosing under fasting conditions, alternate-day dosing, and co-administration with vitamin C or a meat protein. This review focuses on current recommendations and evidence supporting alternate-day oral iron dosing as a strategy to mitigate hepcidin-mediated reductions in absorption in patients with iron deficiency and IDA.

Evidence for Alternate Day Dosing
Guidelines from the American College of Gastroenterology and the European Hematology Association, both published in 2024, recommend alternate-day administration of oral iron as a strategy to improve tolerability and adherence without compromising hematologic response.4,5 Likewise, a 2025 expert consensus on iron deficiency management, convened by the Iron Consortium at Oregon Health & Science University, unanimously recommended alternate-day dosing in cases where daily oral iron is poorly tolerated due to GI AEs.6 The panel concluded that the benefits of alternate-day dosing, particularly reduced incidence of AEs, outweigh the potential risk of undertreatment in patients unable to tolerate daily therapy.

The recommendation in the 2025 consensus panel was based on very low-certainty evidence from 3 randomized controlled trials (RCTs), 1 of which did not report hemoglobin outcomes, while the other 2 found no significant difference in hemoglobin levels between daily and alternate-day iron dosing.6 These trials were included in a systematic review by Kamath et al (2024), which compared the efficacy and safety of daily versus alternate-day oral iron therapy in individuals aged 10 years and older with IDA.7 IDA was defined as hemoglobin ≤13 g/dL in men, ≤12 g/dL in women and adolescents aged 12 years and older, and ≤11.5 g/dL in adolescents aged 10 to 11 years. The review included 7 studies published between 2000 and 2023 (5 RCTs and 2 quasi-experimental studies) with a total of 544 participants (sample sizes, 19 to 200; mean ages, 21 to 49 years). Four of the 7 studies enrolled only women of reproductive age. Most studies used oral ferrous sulfate at doses of 60 to 200 mg elemental iron per dose, administered daily or on alternate days for 2 weeks to 2 months. The primary outcome was change in hemoglobin level, with secondary outcomes including changes in other iron indices such as ferritin, hepcidin, total iron-binding capacity, and reticulocyte count.

Due to heterogeneity among the included studies, a meta-analysis was not performed.7 Across trials, both daily and alternate-day regimens significantly improved hemoglobin levels from baseline, but the authors noted that between-group differences were generally nonsignificant, except for one study reporting greater improvement with daily dosing at 3 weeks (mean hemoglobin increase, 1.6 vs 1.1 g/dL; p = 0.02) and 6 weeks (2.9 vs 2.0 g/dL; p = 0.03). Iron absorption and ferritin improvements were also reported to be similar between dosing strategies. Interestingly, only one study found that hepcidin increases were significantly greater with daily dosing, whereas the others reported no significant differences in hepcidin levels between groups. As expected, common GI AEs such as nausea, metallic taste, and constipation were less frequent with alternate-day dosing.

Another systematic review included 11 randomized trials (N=1014) published through March 2025 with oral iron therapy durations ranging from 3 weeks to 6 months.8 Two trials enrolled healthy individuals, while the remainder included patients with IDA. The pooled mean hemoglobin values were similar for daily dosing (12.84 g/dL) and alternate-day dosing (12.52 g/dL; mean difference [MD], 0.28 g/dL; 95% CI, -0.01 to 0.56). Furthermore, subgroup analyses stratified by baseline iron status showed no significant differences between dosing groups in iron-deficient patients (MD, 0.16 g/dL; 95% CI, -0.10 to 0.42) or in non-iron-deficient patients (MD, 1.68 g/dL; 95% CI, -1.23 to 4.60). Changes in other iron indices, including serum iron, ferritin, transferrin saturation, and total iron-binding capacity, also did not differ significantly between groups. Adverse effects were similar (risk ratio, 1.07; 95% CI, 0.86 to 1.34), although the risk of metallic taste was greater with daily dosing (risk ratio, 1.53; 95% CI, 1.21 to 1.94). Overall, certainty of evidence was rated very low for most outcomes due to heterogeneity and imprecision.

Following the publication of the 2024 systematic review and 2025 meta-analysis, 3 international RCTs further evaluated daily versus alternate-day oral iron dosing, finding mixed but generally supportive findings for alternate-day regimens (See Table 1).9-11 Across adult and pediatric populations, alternate-day administration was at least as effective as daily dosing for improving hemoglobin, with evidence of greater early hematologic response when hemoglobin was measured approximately 1 month after therapy initiation in patients with established anemia.9,10 Short-term hemoglobin changes assessed at 2 weeks were similar in iron-deficient populations without anemia; however, this follow-up duration may be insufficient to detect changes in hemoglobin, which are typically recommended to be assessed at least 1 month after initiation of iron therapy.3-5,11 Importantly, one study with ferrous sulfate and one with ferrous fumarate demonstrated better GI tolerability with alternate-day regimens, without compromising adherence.9,10 Effects on hepcidin were variable and did not uniformly favor one strategy, indicating that biochemical changes may potentially depend on patient population, iron formulation, and/or study duration.9-11 Overall, these studies support alternate-day dosing as a reasonable and likely better-tolerated alternative to daily oral iron, particularly in patients with IDA when early response and GI AEs are key considerations.

Table 1. Newer studies comparing daily vs alternate day dosing of oral iron.9-11
StudyDesign and populationIron RegimensKey Laboratory ChangesSide Effects / Tolerability
Dhanush et al, 20259 (India)OL, RCT in women with IDA (Hg 6 to 10 g/dL and ferritin <30 mcg/L)

Duration: up to 8 weeks		FeSO4 120 mg QOD (n=34)

FeSO4 60 mg QD (n=34)		Primary:

Hgb on Day 28: significantly improved in the QOD vs QD group
(mean change: +2.2 ± 1.3 vs +1.3 ± 1.1 g/dL, p=0.003)

Other:

Hgb on Day 56: difference between QOD and QD groups did not reach statistical significance
(mean change: +3.4 ± 1.7 vs +2.2 ± 1.4 g/dL, p=0.11)

Hepcidin on Day 14: no significant difference between QOD and QD groups
(median [IQR] change: −0.8 ng/mL [−7.5 to +2.9] vs +0.3 ng/mL [−4.95 to +4.4]; p>0.05)		Fewer AEs with QOD (9%) vs QD (45%) during first 4 wks.

Treatment compliance was >90% in both groups.
Grover et al 202510 (India)OL, RCT in children aged 6 months to 10 years with IDA

Duration: up to 30 days		Ferrous fumarate 4 mg/kg single dose QOD (n=20)

Ferrous fumarate 4 mg/kg/day divided in 2 doses (n=20)		Mean (± SD) Hgb at Day 30 was greater with QOD vs daily dosing (10.41 ± 1.32 vs 8.89 ± 1.38 g/dL; p<0.001)

Mean (± SD) hepcidin levels 48 hours after dosing were higher in the daily vs QOD dosing group (7.87 ± 5.56 vs 4.1 ± 2.75; p=0.010)		Fewer GI AEs in the QOD vs daily group (20% vs 60%; p=0.010)
John et al, 202511
(India)		DB, NI, RCT in women with ID (ferritin < 20 mcg/L); at baseline, 56.6% of patients in the QOD group and 50% of patients in QD group had anemia

Duration: up to 14 days		FeSO4 120 mg QOD (n=30)

FeSO4 60 mg QD (n=30)		Outcomes at day 14:

Hgb was similar in QOD and QD groups (12.1 vs 12.15 g/dL; p=0.75)

The rate of anemia (Hgb <12 g/dL) was similar in the QOD and QD groups (56.6% vs 40%; p=1.0)

The rate of ID was similar in the QOD and QD groups (56.5% vs 60%; p=0.79)

Hepcidin levels were similar in the QOD and QD groups (13.40 and 14.88 ng/dL; p=0.32)		No statistically significant difference between groups in the rate of AEs.

Adherence was ≥95 % in both groups.
Abbreviations: AE: adverse event; DB: double‑blind; FeSO4: ferrous sulfate; GI: gastrointestinal; Hgb: hemoglobin; ID: iron deficiency; IDA: iron deficiency anemia; IQR: interquartile range; NI: non‑inferiority; OL: open‑label; QD: once daily; QOD: every other day; RCT: randomized controlled trial; SD: standard deviation; wks: weeks.

Summary
Guidelines for the management of IDA recommend alternate-day dosing in cases where daily oral iron is poorly tolerated due to GI AEs. A 2024 qualitative systematic review, 2025 meta-analysis, and 3 newer randomized trials generally support these recommendations, finding that alternate-day dosing likely improves GI tolerability. Findings are less certain regarding whether alternate-day dosing improves hematologic response; however, available data suggest that hematologic outcomes are at least comparable to those achieved with daily dosing.

References:

  1. Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther. 2024;9(1):271. Published 2024 Oct 14. doi:10.1038/s41392-024-01969-z
  2. Andrade C. Dosing Patients With Oral Iron Supplements: Practical Guidance. J Clin Psychiatry. 2025;86(4):25f16139. Published 2025 Oct 8. doi:10.4088/JCP.25f16139
  3. Ko CW, Siddique SM, Patel A, et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020;159(3):1085-1094. doi:10.1053/j.gastro.2020.06.046
  4. DeLoughery TG, Jackson CS, Ko CW, Rockey DC. AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review. Clin Gastroenterol Hepatol. 2024;22(8):1575-1583. doi:10.1016/j.cgh.2024.03.046
  5. Iolascon A, Andolfo I, Russo R, et al. Recommendations for diagnosis, treatment, and prevention of iron deficiency and iron deficiency anemia. Hemasphere. 2024;8(7):e108. Published 2024 Jul 15. doi:10.1002/hem3.108
  6. Benson AE, Lo JO, Achebe MO, et al. Management of iron deficiency in children, adults, and pregnant individuals: evidence-based and expert consensus recommendations. Lancet Haematol. 2025;12(5):e376-e388. doi:10.1016/S2352-3026(25)00038-9
  7. Kamath S, Parveen RS, Hegde S, Mathias EG, Nayak V, Boloor A. Daily versus alternate day oral iron therapy in iron deficiency anemia: a systematic review. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(5):2701-2714. doi:10.1007/s00210-023-02817-7
  8. Dhanvijay AD, Patidar V, Singh J, et al. Efficacy of daily versus alternate day oral iron supplementation for management of anaemia among general population: a systematic review and meta-analysis. BMC Pharmacol Toxicol. 2025;26(1):152. doi:10.1186/s40360-025-00984-2
  9. Dhanush M, Vinod KV, Manivannan P, Adole PS, Govindan D. Daily Versus Alternate Day Oral Iron Replacement for Women with Iron Deficiency Anaemia: A Randomized Controlled Trial. Indian J Hematol Blood Transfus. 2025;41(2):245-251. doi:10.1007/s12288-024-01816-9
  10. Grover P, S A. Efficacy of alternate day versus daily oral iron therapy in children with iron deficiency anemia: a randomized controlled trial. Int J Hematol. 2025;122(6):893-900. doi:10.1007/s12185-025-04048-3
  11. John NM, Ashok B, John O, et al. Daily oral iron supplementation produced greater improvements in hematological parameters than alternate day doses – A pilot double-blind randomized control trial in iron-deficient young women. Clin Nutr. Published online November 25, 2025. doi:10.1016/j.clnu.2025.11.005

Prepared by:
Kathy Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

February 2026

The information presented is current as of January 20, 2026. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.